The relationship between serum alkaline phosphatase levels and sepsis: observational and Mendelian randomization studies

Abstract

Aim: There is no definitive evidence to establish a causal relationship between elevated serum alkaline phosphatase (ALP) levels and sepsis susceptibility. This study employed observational and Mendelian randomization (MR) studies to investigate their potential correlation.

Methods: This observational study used data from the eICU Collaborative Research Database (eICU-CRD) and included adult patients who were admitted to the ICU for a single episode, with an ICU stay of ≥ 24 h, and serum ALP records obtained within 24 hours of admission. Based on three quantiles of ALP, participants were divided into three groups (Units/L): ALP ≤ 59, 60 ≤ ALP ≤ 86, and ALP ≥ 87. Multivariate logistic regression (MLR) explored the association between serum ALP levels and sepsis susceptibility in the general population and subgroups categorized by sex, age, blood lactate, and APACHE IV scores. Meanwhile, this study utilized genome-wide association studies (GWAS) data of serum ALP levels (Neale lab, n = 13,586,006) and sepsis (UK Biobank, n = 12,243,539) to conduct MR analysis to validate their causal relationship by the inverse variance weighted (IVW) method.

Results: The observational study comprised 4,458 patients. The sepsis susceptibility of the three groups was 11.1%, 12.5%, and 17.4%, respectively. MLR analysis revealed that sepsis susceptibility of the ALP ≥ 87 group was 1.748 times higher than the ALP ≤ 59 group (OR = 1.748, 95%CI: 1.399-2.183). There was a consistent correlation between them in sex, age, blood lactate, and the APACHE IV scores subgroup. MR study demonstrated a causal association between them (OR = 1.005, 95%CI: 1.002-1.008).

Conclusions: Elevated serum ALP levels are significantly associated with sepsis susceptibility, and there is a causal relationship between them.

Keywords

Alkaline phosphatase / sepsis / observational study / Mendelian randomization study / biomarker

References

[1] SingerM,SeymourCW.The third international consensus definitions for sepsis and septic shock (Sepsis-3).JAMA2016;315:801-10

[2] RuddKE,AgesaKM.Global, regional, and national sepsis incidence and mortality, 1990-2017: analysis for the Global Burden of Disease Study.Lancet2020;395:200-11

[3] HuangM,SuJ.The Pathogenesis of sepsis and potential therapeutic targets.Int J Mol Sci2019;20:5376 PMCID:PMC6862039

[4] RocheteauP,BriandD.Sepsis induces long-term metabolic and mitochondrial muscle stem cell dysfunction amenable by mesenchymal stem cell therapy.Nat Commun2015;6:10145 PMCID:PMC4682118

[5] SinghSB.Role of intestinal alkaline phosphatase in innate immunity.Biomolecules2021;11:1784 PMCID:PMC8698947

[6] HanY,LiZ,QiuH.Recent progress and prospects of alkaline phosphatase biosensor based on fluorescence strategy.Biosens Bioelectron2020;148:111811

[7] Iluz-FreundlichD,UhanovaJ,KnowlesC.Low serum alkaline phosphatase levels in patients with chronic liver diseases: Possible contributions to disease pathogenesis.Clin Res Hepatol Gastroenterol2021;45:101694

[8] LeeJH,LeeYJ.Relationship between serum alkaline phosphatase and low muscle mass index among Korean adults: a nationwide population-based study.Biomolecules2021;11:842 PMCID:PMC8226801

[9] KunutsorSK,KhanH.Liver enzymes and risk of cardiovascular disease in the general population: a meta-analysis of prospective cohort studies.Atherosclerosis2014;236:7-17

[10] CheungBM,WongLY.Elevated serum alkaline phosphatase and peripheral arterial disease in the United States National Health and Nutrition Examination Survey 1999-2004.Int J Cardiol2009;135:156-61

[11] KimJH,ParkHM.Serum alkaline phosphatase level is positively associated with metabolic syndrome: a nationwide population-based study.Clin Chim Acta2020;500:189-94

[12] MirjačićMartinović K,TišmaMiletić N.Increased circulating monocyte MDSCs positively correlate with serum Interleukin-10 in metastatic melanoma patients.Innate Immun2023;29:37-44 PMCID:PMC10331212

[13] KatasakoA,RaitaY.Association between serum alkaline phosphatase and bacteraemia in haemodialysis outpatients: a multicentre retrospective cross-sectional study.BMJ Open2022;12:e058666 PMCID:PMC9557305

[14] CheungBM,CheungRV.Association between plasma alkaline phosphatase and C-reactive protein in Hong Kong Chinese.Clin Chem Lab Med2008;46:523-7

[15] KernerA,SellaR.Association between elevated liver enzymes and C-reactive protein: possible hepatic contribution to systemic inflammation in the metabolic syndrome.Arterioscler Thromb Vasc Biol2005;25:193-7

[16] EmdinCA,KathiresanS.Mendelian randomization.JAMA2017;318:1925-6

[17] CohenJC,MosleyTH Jr.Sequence variations in PCSK9, low LDL, and protection against coronary heart disease.N Engl J Med2006;354:1264-72

[18] LiX,HawkinsGA.eQTL of bronchial epithelial cells and bronchial alveolar lavage deciphers GWAS-identified asthma genes.Allergy2015;70:1309-18

[19] ZengL,ChenJ.Causal association of lipoprotein-associated phospholipids on the risk of sepsis: a Mendelian randomization study.Front Endocrinol2023;14:1275132 PMCID:PMC10808779

[20] HuY,MaoH,CuiY.Causal effects of genetically predicted iron status on sepsis: a two-sample bidirectional Mendelian randomization study.Front Nutr2021;8:747547 PMCID:PMC8639868

[21] ZhangZ,ChenT.Investigating the impact of human blood metabolites on the Sepsis development and progression: a study utilizing two-sample Mendelian randomization.Front Med2023;10:1310391 PMCID:PMC10748392

[22] ZhiF,JiDD,LiQQ.Causal associations between circulating cytokines and risk of sepsis and related outcomes: a two-sample Mendelian randomization study.Front Immunol2024;15:1336586 PMCID:PMC10948396

[23] FangW,LuJ.The causal effects of circulating cytokines on sepsis: a Mendelian randomization study.PeerJ2024;12:e16860 PMCID:PMC10838533

[24] PollardTJ,RaffaJD,MarkRG.The eICU Collaborative Research Database, a freely available multi-center database for critical care research.Sci Data2018;5:180178 PMCID:PMC6132188

[25] SkrivankovaVW,WoolfBAR.Strengthening the reporting of observational studies in epidemiology using mendelian randomization: the STROBE-MR statement.JAMA2021;326:1614-21

[26] HemaniG,ElsworthB.The MR-Base platform supports systematic causal inference across the human phenome.eLife2018;7:e34408

[27] KamatMA,YoungR.PhenoScanner V2: an expanded tool for searching human genotype-phenotype associations.Bioinformatics2019;35:4851-3

[28] BurgessS.Bias in causal estimates from Mendelian randomization studies with weak instruments.Stat Med2011;30:1312-23

[29] BurgessS.Interpreting findings from Mendelian randomization using the MR-Egger method.Eur J Epidemiol2017;32:377-89

[30] BowdenJ,MinelliC.Improving the accuracy of two-sample summary-data Mendelian randomization: moving beyond the NOME assumption.Int J Epidemiol2019;48:728-42 PMCID:PMC6659376

[31] BowdenJ,BurgessS.Mendelian randomization with invalid instruments: effect estimation and bias detection through Egger regression.Int J Epidemiol2015;44:512-25 PMCID:PMC4469799

[32] ZhangCY,ZhaoSL.Clinical value of alkaline phosphatase on the surface membrane of neutrophils for prediction of bacteremia in patients with systemic inflammatory response syndrome.Diagn Microbiol Infect Dis2021;100:114105

[33] ParkHM,LeeYJ.Positive association of serum alkaline phosphatase level with severe knee osteoarthritis: a nationwide population-based study.Diagnostics2020;10:1016 PMCID:PMC7760969

[34] WebberM,ThomasNG.Association between serum alkaline phosphatase and C-reactive protein in the United States National Health and Nutrition Examination Survey 2005-2006.Clin Chem Lab Med2010;48:167-73